Preliminary results generated in the laboratories of Dr. Madsen and his collaborator, Dr. Russell, suggest that while transplant arteriopathy requires histoincompatibility between donor and recipient, it can occur in tolerant recipients and even in recipients devoid of any adaptive immune response, either cellular or humoral. This finding suggests that additional mechanisms beyond conventionally characterized cellular and humoral immune responsiveness may be important factors leading to vasculopathy. The proposed research explores the strong possibility that innate immunity, specifically the cytotoxicity or cytokine release properties of NK cells, contributes to the pathogenesis of cardiac allograft vasculopathy (CAV). The involvement of innate responsiveness may represent an additional, or parallel, mechanism for the production of vasculopathy, and one that is not be targeted by current immunosuppressive therapy. Our principle aim is to fully characterize the role of NK cells and macrophages in the pathogenesis of CAV in the biologically simple setting of parental to F1 transplants in mice, and in combinations involving non-reactive (RAG1-/-) mice. These experiments will include in vitro assays of NK cell numbers and function. Since the innate immune system is thought to remain functional in chronically immunosuppressed recipients, a study of its role in the formation of chronic vasculopathy is clinically relevant.